The overall goal of this project is to elucidate how anti- and pro-atherogenic factors modulate nuclear factor (NF)-:B activation to influence vascular inflammation and atherogenesis. A major hypothesis is that extracellular signal-regulated kinase (ERK) and p38 MAPK signaling pathways inversely regulate the duration and amplitude of NF-:B activation induced by cytokines, which influences atherogenesis. This proposal is focused on 3 specific aims: 1. To elucidate how MAPKs regulate interleukin-12-induced NF-:B activation and gene expression. The proposed studies will determine (i) how RSK1, a kinase downstream of ERK, and I:B kinases regulate the duration and amplitude of NF-:B activation through phosphorylation of I:B proteins;(ii) whether p38 mediates the effects of vasoconstrictors such as angiotensin II and thromboxane receptor agonists on the relative expression of NF-:B-dependent genes by acting on MAPK phosphatases, protein phosphatase-1/2A, or heat shock protein-27. 2. To elucidate how the relative expression of VCAM-1 and iNOS represented distinct NF-:B-dependent genes in aortic smooth muscle influence atherogenesis. The proposed studies aim to (i) elucidate the in vivo roles of MAPKs in mediating vasoconstrictors regulation of VCAM-1 and iNOS expression in smooth muscle;(ii) target differential regulation of VCAM-1 and iNOS represented gene expression in atherosclerotic animal models to explore how relative changes correlate with atherosclerosis;(iii) determine the roles of smooth muscle cell iNOS and VCAM-1 expression in controlling foam cell formation, an important marker of atherogenesis. 3. To elucidate the roles of I:B1- and I:B2-mediated inflammatory responses in atherogenesis. The hypothesis is that differential regulation of IkB1- and I:B2-mediated NF-:B activation is critical to atherogenesis. The proposed studies will (i) use I:B1- or I:B2-deficient cells to examine ERK-dependent NF- :B-mediated gene expression;and (ii) examine selected inflammatory events and atherogenesis in wild type and I:B1 knock-out/I:B2 knock-in mice on an atherogenic diet either with or without angiotensin II infusion. It is expected that defining mechanisms by which ERK and p38 MAPK signaling pathways regulate the duration and amplitude of NF-:B activation will help design novel therapeutic strategies to treat and prevent atherosclerosis. It is relevant to the mission of the NIH. Project Narrative Activation of nuclear factor: B is critical for vascular inflammation and atherosclerosis. This proposal aims to elucidate the mechanism by which anti- or pro-atherogenic factors modulate nuclear factor-:B activation to influence vascular inflammatory process, which will help design novel therapeutic strategies to treat and prevent atherosclerosis.